Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy

• Published in: JHEP reports 2023-10, Vol.5 (10), p.100844, Article 100844
• Main Authors: Gonzales, Emmanuel, Gardin, Antoine, Almes, Marion, Darmellah-Remil, Amaria, Seguin, Hanh, Mussini, Charlotte, Franchi-Abella, Stéphanie, Duché, Mathieu, Ackermann, Oanez, Thébaut, Alice, Habes, Dalila, Hermeziu, Bogdan, Lapalus, Martine, Falguières, Thomas, Combal, Jean-Philippe, Benichou, Bernard, Valero, Sonia, Davit-Spraul, Anne, Jacquemin, Emmanuel
• Format: Article
• Language: English
• Subjects: ABCB4; Biliary lithiasis; Hepatocellular carcinoma; Intrahepatic cholestasis of pregnancy; Liver transplantation; MDR3
• ISSN: 2589-5559; 2589-5559
• DOI: 10.1016/j.jhepr.2023.100844

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to UDCA therapy on long-term outcome are scarce. We describe retrospectively a cohort of 38 PFIC3 patients with a median age at last follow-up of 19.5 years (3.8-53.8). Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplantation (LT) at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with a positive (normal or decreased) MDR3 canalicular expression in native liver and had a prolonged native liver survival (NLS; median: 12.4 years (3.8-53.8)). In contrast, patients with severe genotypes (no missense variation) had no detectable MDR3 canalicular expression, earlier symptom onset and age at cirrhosis and all underwent LT at a median age of 6.7 years (range: 2.3-10.3). The former group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed a liver biochemistry improvement. Biliary phospholipid level over 6.9% of total biliary lipids predicted response to UDCA therapy. Response to UDCA predicted NLS. Patients carrying at least one missense variation, with a positive MDR3 canalicular expression, and a biliary phospholipid level over 6.9% were more likely to respond to UDCA therapy and to exhibit prolonged NLS. In this study, data show that genotype and response to UDCA therapy predicted nature liver survival of PFIC3 patients. Patients carrying at least one missense variation, with a positive (decreased or normal) MDR3 canalicular immuno-staining, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to UDCA therapy and to exhibit prolonged native liver survival. [Display omitted] •71% of patients had cirrhosis at a median age of 8.1 years of whom 66% received a liver transplant at a median age of 8.5 years.•Patients with severe genotype (no missense variation) did not response to UDCA treatment.•87% of patients with at least one missense variation responded partially or fully to UDCA treatment.•Biliary phospholipid level over 6.9% of total biliary lipids predicted response to UDCA therapy.•Severity of gentotypes and